Relaxation to authentic nitric oxide and SIN‐1 in rat isolated mesenteric arteries: variable role for smooth muscle hyperpolarization

Abstract

1 Authentic nitric oxide (NO; 0.1 ± 10 mmoles) caused transient, dose-dependent relaxation of phenylephrine-induced tone without changing membrane potential in mesenteric arteries. Larger doses, above 10 mmoles, did not evoke more relaxation (maximal relaxation to 150 mmoles NO in denuded arteries, 69+7%, n=8) but stimulated muscle hyperpolarization (maximum 19+3 mV, n=5). 2 The soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 mM), abolished relaxation to low doses of NO (n=4), but did not modify hyperpolarization with higher doses of NO (n=4). The potassium channel blocker charybdotoxin (ChTX; 50 nM) abolished hyperpolarization to high doses of NO and signi®cantly reduced the maximal relaxation (to 43+6%, n=4; P50.01). ODQ and ChTX together abolished tension and membrane potential change to all doses of NO (n=4). 3 All relaxations to 3-morpholino-sydnonimine (SIN-1; 0.01 ± 10 mM) were associated with hyperpolarization. When the endothelium was intact, ChTX inhibited hyperpolarization and relaxation to SIN-1 (n=5), while iberiotoxin (IbTX; 50 nM) or 4-aminopyridine (4-AP; 500 mM) reduced relaxation by 40% and 20%, respectively and by 80% in combination (n=6 in each case). 4 In denuded arteries, relaxation to SIN-1 was una ected by either ChTX or ODQ alone, but abolished by the inhibitors together (n=6). Alone, 4-AP did not alter relaxation, but in the presence of ODQ it reduced the maximal response by around 45% (n=6; P50.01). 4-AP, ODQ and IbTX together inhibited relaxation to SIN-1 by 75% (n=6; P50.01). 5 Therefore, cyclic guanosine 3',5'-monophosphate (cyclic GMP)-independent smooth muscle hyperpolarization, possibly involving direct activation of calcium-activated and voltage-sensitive potassium channels, contributes to relaxation evoked by authentic NO and SIN-1. However, the importance of each pathway depends on the source of NO and with SIN-1 the relative contribution from each pathway is modi®ed by the endothelium.

NO − Activates Soluble Guanylate Cyclase and K v Channels to Vasodilate Resistance Arteries

“…33 Taken together with our findings, it may be suggested that NO ⅷ and NO Ϫ can mediate vasorelaxation of resistance arteries through distinct mechanisms, namely, the activation of K Ca and K v channels, respectively. These findings are of particular importance in light of the recent reports that the activity of endothelium-derived relaxing factor in large conduit arteries 4,5 more closely resembles the properties of NO Ϫ rather than NO ⅷ .…”

Mechanisms of nitric oxide-mediated, neurogenic vasodilation in mesenteric resistance arteries of toad Bufo marinus

“…In arterial smooth muscle, one of the major intracellular facilitators of NO-mediated vasodilation is K ϩ channels (43). In mammalian mesenteric arteries, it has been shown that NO-mediated vasodilation is caused, in part, by opening of Ca 2ϩ -activated K ϩ (K Ca ) (11,30,38,52,62) and voltage-gated K ϩ (K V ) (27,68) channels. In toad, clotrimazole, an inhibitor of large-conductance K Ca (BK Ca ) channels, intermediate-conductance K Ca (IK Ca ) channels, and K V channels (58) significantly decreased the AChinduced vasodilation that is attributed to NO.…”

Redox variants of NO (NO· and HNO) elicit vasorelaxation of resistance arteries via distinct mechanisms

“…However, we have identified an apparent ability of exogenous (18) and endogenous (2) HNO to activate voltage-dependent K ϩ (K v ) channels in the resistance vasculature. In contrast, NO ⅐ targets Ca 2ϩ -activated K ϩ (K Ca ) channels in the same preparation (34). Such distinct actions of these NO redox siblings may facilitate the use of HNO donors over traditional nitrovasodilators for the treatment of vascular dysfunction.…”